Detecting the onset of accelerated long-term forgetting: evidence from temporal

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Detecting the

onset of accelerated long
-
term forgetting
: evidence from
temporal
lobe epilepsy.


Terence McGibbon

&

Ashok S
.

Jansari


School of Psychology, University of East London,
Water Lane, London E15 4LZ, UK


Short Title:
Onset of
Accelerated
Long
-
term Forgetting and Epilepsy

Running Head: Accelerated Long
-
term Forgetting


Address for correspondence:

Terence McGibbon

School of Psychology

University of East London

Water Lane

London

E15 4LZ

UK

Tel: +44 (0)
7990 787075

Fax: +44 (0)20 8223 4937

Ema
il:
t.mcgibbon@uel.ac.uk

RUNNING HEAD: ACCELERATED LONG
-
TERM FORGETTING


2

Abstract

Accelerated Long
-
term Forgetting (ALF) refers to a slowly developing anterograde amnesia
in which material is retained normally over short delays but then forgotten at an abnormally
fast rate over days to weeks. Such long
-
term memory impairment is not dete
cted by standard
clinical tests. This study
analysed

ALF in a temporal lobe epilep
tic, RY. Key issues
addressed w
ere: (i) the timeframe of ALF onset; (ii) whether
disruption of memory
consolidation during
sleep is a necessary requirement for
precipitating
ALF; (iii) the
effectiveness of repeated recall in limiting the impact of ALF. RY’s memory for
novel
word
-
pairings was compared with that of matched controls using cued
-
recall and forced choice
recognition (FCR) tests at multiple delays (5, 30, 55, 240 min
). To investigate
the
impact of
repeated recall some pairings were recalled at all intervals
,

and all material
(repeatedly and
non
-
repeatedly recalled)
was tested again after a 24 hour delay.
RY’s initial learning and
performance at 30 min were normal, but

by 55 min both his cued
-
recall performance and the
subjective quality of his recognition memory were significantly impaired
.
This suggests
disruption of secondary consolidation processes occur
ring

relatively soon after learning. It
also raises the possibi
lity of developing a standard test to diagnose AL
F within a single
clinical session rather than requiring multiple visits
.
Since RY remained awake it appears
that

disruption of memory consolidation
during sleep

is not a necessary condition for him to
experience ALF.
Repeated recall

at multiple time
-
points within the first 4 hours
sustained

normal
recall
performance
to

24 hours, indicating repeated recall could form the basis for a
protective strategy.


Keyword
s: Accelerated long
-
term forgetting

(ALF)
, Long
-
term amnesia

(LTA)
,
Temporal lobe epilepsy, Medial temporal lobe, Recollection, Long
-
term memory

RUNNING HEAD: ACCELERATED LONG
-
TERM FORGETTING


3

1. Introduction

The traditional view
of memory consolidation as
a single stage process
that converts

short term memories into a form in which they can be retained for long periods (Weingartner
& Parker, 1984)

has come under attack in recent decades
.
T
here is mounting evidence that
such a
single stage model may be inadequate.

One such line of evidence com
es from the
study of patients displaying a form of amnesia referred to as

“long
-
term amnesia” (LTA;
Kapur et al., 1997), or “accelerated long
-
term forgetting” (ALF; Butler

&

Zeman, 200
8
).
In
contrast to the classical amnesic syndrome, in which memory is im
paired within minutes,
patients suffering from ALF show relatively normal acquisition and initial retention of new
information and perform within the normal range for standard neuropsychological tests at
delays of up to 30minutes. However, they then displa
y accelerated forgetting of the same
information over periods of hours to weeks (Ahern et al., 1994;
Blake, Wroe, Breen, &
McCarthy, 2000; Butler et al., 2007, 2009; Jansari, Davis, McGibbon, Firminger, & Kapur,
2010; Kapur et al., 1996, 1997; Mameniskiene
, Jatuzis, Kaubrys, & Budrys, 2006; Mayes et
al., 2003;
Muhlert et al., 2011;
Muhlert, Milton, Butler, Kapur, & Zeman, 2010; O’Connor,
Sieggreen, Ahern, Schomer, & Mesulam, 1997). This pattern of forgetting suggests the
existence of secondary consolidation

processes, occurring at time frames beyond the 30
minute interval of standard clinical tests, which

are necessary to convert memories

into a
form suited to long term retention. A failure of these processes could explain
the distinctive

forgetting pattern
found in ALF.

In a review of ALF cases known at the time, Mayes et al. (2003) highlighted
the fact
that
although cases had arisen from
multiple aetiologies (including anoxia, encephalitis and head
injuries) either epi
lep
sy or temporal cortex damage, or bo
th, were present in most cases, while
medial temporal lobe (MTL) damage was rare.
This is significant as there is
evidence that
some forms of memory are dependent on the MTL initially but become less reliant on this
structure over time through secondary
consolidation processes (e.g. temporal gradients in
retrograde amnesia in cases of MTL damage; Zolan
-
Morgan, Squire, & Amaral, 1986)
.

Mayes
RUNNING HEAD: ACCELERATED LONG
-
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4

et al.
(2003)
speculate that, in the case of ALF, an intact MTL enables the initial consolidation
of information, wh
ile disruption of either the transfer to long term neocortical storage sites, or
the maintenance
of information
within these sites, results in forgetting. They discuss structural
damage and disruption of consolidation processes by epileptiform activity as
possible causes.

Further evidence of a link between epilepsy and ALF comes from symptoms reported by
patients suffering from temporal lobe epilepsy (TLE). Such patents often complain of severe
memory problems, yet perform well in standard neuropsychologi
cal tests that measure
anterograde memory retention over delays of up to 30 minutes (Blake et al., 2000; Corcoran &
Thompson, 1992; Mameniskiene et al., 2006; Martin, Loring, Meador & Gregory, 1988).

One
possible explanation is that standard tests may be i
nsufficiently sensitive to detect mild deficits
in early processing (Butler & Zeman, 2008). An alternative possibility

is that the standardised
test delay of 30 minutes is too short to detect a long
-
term recall impairment which these
patients suffer from,
and that this ALF is ultimately as detrimental to everyday living as the
impairments of immediate and delayed recall measured by the standard tests.
The p
resence of
ALF in this patient group
has been confirmed by group st
udies
(Blake et al., 2000;
Mamenis
kiene et al., 2006;
Muhlert et al., 2011;
Wilkinson

et al., 20
12
).
In the largest
study,
Mameniskiene et al. (2006) compared 70 TLE patients with matched controls, using recall at
30 minutes and 4 weeks to provide a measure of long
-
term retention. They fou
nd that the
number of seizures during the study and the age of the patient were significant predictors of
accelerated forgetting. A further notable predictor was the presence of sub
-
clinical epileptic
activity as measured by EEG.

Wilkinson et al. (2012)

al
so
found evidence that

long
-
term
forgetting was associated with frequency of seizures
, but in addition found that hippocampal
pathology in patients with TLE can cause deficits in acquiring new memories and retaining
these over short delays
.

Muhlert et al.
(2011)

found
evidence of ALF in TLE cases but not in
cases of idiopathic generalised epilepsy, indicating
that only epilepsy with tempor
al lobe
involvement contributes
to ALF.


RUNNING HEAD: ACCELERATED LONG
-
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5

A final line of evidence linking epilepsy and ALF comes from

patients wit
h Transient
Epileptic Amnesia (TEA), a condition which is
often accompanied by ALF. In a review of
ALF in cases of TEA, Butler and Zeman (2008) highlight both sub
-
clinical epileptiform
activity and structural damage as likely causal factors. Clinically
apparent seizures are not a
necessary condition for ALF as the patients in several reported TEA studies were seizure free
(e.g. Butler et al., 2007).

In the vast majority of cases where epilepsy was present, patients were taking anti
-
epileptic drugs (AEDs)

at the time of testing. This suggests medication as a further possible
causal factor

due to the amnestic effects that have been associated with these drugs.
(Jokeit,
Kramer & Ebner, 2005)

However
Jansari

et al.
, (2010) report a case of temporal lobe epilep
sy
(TLE) where ALF was clearly detected both before and after medication, and TEA patients
subjectively report ALF symptoms prior to onset of medication and often report improvements
after treatment (Butler et al., 2007).

In addition to its cause, several
other aspects of ALF remain undetermined. Firstly, the
timeframe of onset is unclear. Previous studies
which have found intact memory performance
at short delays
have typically tested memory at 30 minutes, finding no impairment, and then
again after a sing
le extended delay of between 24 hours (e.g. Martin et al., 1991) and 8 weeks
(Blake

et al.
, 2000). Even where testing has been performed at multiple time points, to try to
identify the timescale of ALF occurrence, the shortest extended delay has been 24 ho
urs
(Jansari

et al.
, 2010; Muhlert, Milton, Butler, Kapur, & Zeman, 2010).
Wilkinson et al. (2012)
found evidence of accelerated forgetting at 1 hour. However, as their patients displayed
impaired initial learning and were not tested using standardized mea
sures at 30 minutes it is
not clear that their forgetting at the 1 hour interval meets the normal criteria for ALF.
Overall,
it is clear that
further detailed study of ALF during the first 24 hours will be necessary to
pinpoint the timing of onset and prof
ile its development.

Secondly, the role of sleep in ALF requires further study.
Sleep has been found to improve
performance of newly learnt perceptual
,

motor
and virtual navigation
tasks (Walker,
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-
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6

Brakefield, Morgan, Hobson & Stickgold, 2002
; Peigneux et
al., 2004
), and to improve
recognition memory for newly learnt spoken language material (Fenn, Nusbaum &
Margollash, 2003) and
recall of
word
-
pair associations (Ellenbogen, Hulbert, Stickgold,
Dinges & Thompson
-
Schill, 2006). Given that
ALF has been detect
ed
at
24 hours, it is
possible that disruption of consolidation processes that occur during the first night’s sleep after
initial learning may contribute to the accelerated forgetting. This is particularly relevant in
cases of TEA where there is a strong a
ssociation between amnesic episodes and waking from
sleep. This has led Butler et al. (2007) to suggest that nocturnal seizure activity may interfere
with consolidation.

However, although there is some evidence
of a link between sleep and
ALF
, additional d
etailed analysis of memory performance during the same waking day as
learning will be required to confirm whether
the proposed
disruption of memory consolidation
processes that occur during
sleep is a necessary requirement for ALF, or merely a contributory

factor.

Thirdly, the use of
repeated recall and rehearsal
as protection against ALF requires further
evaluation. Mayes et al. note that for their patient JL, who suffered from ALF, “greatly over
-
rehearsed semantic memories were invulnerable to the effects

of LTA” (p.595, 2003). This
suggests that rehearsal could form the basis of a memory compensation strategy for ALF
patients. In the first known direct test of
repeated recall
as a protective strategy in a case of
ALF, Jansari

et al.
, (2010) found that memory for repeatedly recalled short stories was
maintained at normal levels to 4 weeks, for both recognition and free
-
recall, while free
-
recall
of non
-
repeatedly recalled stories was significantly impaired
within
24 hours and reached fl
oor
after 2 weeks. This result highlights the importance of further
research

into the benefits for
ALF patients of different forms of
repeated recall or rehearsal
on
retention of
different types of
material.

The current study addressed these three unresolv
ed aspects of ALF by extending an on
-
going case study of a patient RY,
displaying sub
-
clinical TLE and ALF, who has been studied
by Jansari and colleagues since 2003 (e.g.
Jansari et al., 2010
)
.

RY complains of poor sleep
RUNNING HEAD: ACCELERATED LONG
-
TERM FORGETTING


7

patterns, waking early and often s
leeping for only a few hours. When neurologically examined
in 2003 his EEG data showed greater epileptic activity during sleep

than while awake
.
Ellenbogen

et al.
, (2006) showed that sleep protected declarative memories by increasing
immunity to
associative interference. It was speculated that due to sub
-
clinical epileptic
activity RY might not benefit from this memory consolidation during sleep in the way that
normal controls

do
.
This hypothesis was supported by initial work with RY which tested
at an
extended delay of 24 hours, and then at further time points up to 4 weeks (
Jansari et al., 2010)
,
and which found that the most significant loss occurred during the first 24 hours. However a
pilot study using a modified and extended version of Ellenb
ogen et al.’s cued
-
recall of word
-
pair associations procedure found evidence of ALF after 12 hour of wakefulness (
McGibbon,
Jansari & Gaskell, 2008
). This suggested that the onset of RY’s ALF occurs during the same
waking day as learning, and
therefore, ev
en if
disruption of memory consolidation processes
that occur during sleep contributes to his ALF
,

it cannot be the sole cause
.

In the current study the profile of RY’s forgetting during the first few hours
after learning
was examined more closely. A
novel

test procedure was developed to test for cued
-
recall and
forced choice recognition (FCR) of word
-
pair associations at time points of 5 minutes, 30
minutes, 55 minutes

and

4 hours. The impact of repeated recall at all time points was also
investigated, to build on previous evidence (
Jansari

et al., 2010
) that repeated recall of short
stories can limit the effects of
ALF
,

by extending the method to memory for word
-
pair
assoc
iations.


2. Case History

RY, a right handed man born in 1939, presented in 2001 complaining of memory
problems which had started about one year
earlier
. He reported difficulty recalling the
details of events that had occurred more than
about 4
-
6 weeks
previously
. He gave the
example of a
holiday to Hawaii completed a few months earlier. When his wife asked about
RUNNING HEAD: ACCELERATED LONG
-
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8

the trip he claimed that he had never been there.
Looking at photographs from
the holiday
failed to trigger any recollection. Similarly, many social events attended with his wife were
often totally forgotten after 6 months. RY
currently

runs a small software company, and
reported difficulty referring back to work he had done one yea
r previously.
RY also reported
problems navigating by car to places he had been many times in the past. While he was still
able to use map
-
reading skills for successful navigation,
he

could no longer visualize the
route from memory.

Current cognitive funct
ion, as measured by standard neuropsychological testing, was
normal with
the
exception of autobiographical memory (Table 1). RY’s performance on the
AMI (Autobiographical Memory Interview; Kopelman, Wilson, & Baddeley, 1990) was in
the ‘probably abnormal’
or ‘definitely abnormal’ range

for all time periods, and for both
episodic and personal semantic memory.

RY’s
medical

history was
unremarkable with the exception of cardiac
surgery

in 2005
(
Zeman, Boniface, and Hodges (1998)
report
that

a history of
cardiac disease was common
i
n their series of
TEA

patients
). RY also reported experiencing ‘turns’ during which his
awareness changes and he feels a sense of déjà vu. This lasts for about 20 seconds, followed
by a dreamlike episode which can include experi
encing forgotten memories from the past.
These memories can usually be recalled after the ‘turn’, but then fade rapidly. These ‘turns’
had been experienced from childhood. However they had become more frequent
approximately a year before presentation, by w
hich time they were occurring
in clusters of
four or five about twice a month, often in the
morning after

a lack of sleep. No olfactory,
gustatory or epigastric sensations were reported.

A sleep
-
deprived EEG subsequently
identified right

temporal spike activity, with
epileptiform discharges occurring more often

during

sleep than while awake. A
diagnosis of
temporal lobe epilepsy was followed by prescription of anticonvulsant medication
(Lamotrigine, 50mg, twice daily).

RUNNING HEAD: ACCELERATED LONG
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9

A n
europ
sychiatric

evaluation conducted
at
first
diagnosis
failed to identify any
psychosocial causal factors.

MRI investigations at multiple time points since 2001 have
found no evidence
of focal

or
generalised pathology. Figure

1 shows three

coronal slices
through the length of RY’s hippocampi
, taken in 2007. Two independent experts have
judged these images to be structurally normal.


Test

Sub
-
test

RY’s performance

NART (errors = 10)


Pre
-
morbid IQ 118

WAIS
-
R

Performance IQ

124


Verbal IQ


123

WMS
-
R

Stories Immediate Recall

28 (80
th

percentile)


Stories Delayed Recall

25 (82
nd

percentile)


Designs Immediate Recall

36 (95
th

percentile)


Designs Delayed Recall

34 (94
th

percentile)

WMS
-
III

Faces Immediate Retention

41 (scaled score 14)


Faces Delayed Retention

44 (scaled score 18)

Rey
-
Osterieth Figure

Delayed visual recall

70
th

Percentile

WRMT

Faces

67.5
th

Percentile


Words

86.7
th

Percentile

AMI

Childhood semantics

10.5/21 (Definitely abnormal)


Childhood autobiographical

4/9
(Probably abnormal)


Early Adulthood semantics

11.5/21 (Definitely abnormal)


Early Adulthood autobiographical

4/9 (Probably abnormal)


Recent semantics

15/21 (Definitely abnormal)


Recent autobiographical

4/9 (Definitely abnormal)

WSCT


6 Categories
(Normal)

Graded Naming Test


24/30 (Normal)

WAIS
-
R= Wechsler Adult Intelligence Scale Revised; WMS
-
R= Wechsler Memory
Scale Revised; WMS
-
III= Wechsler Memory Scale III; WRMT= Warrington
Recognition Memory Test; AMI= Autobiographical Memory Interview;
WSCT=
Wisconsin Card Sorting Test


Table 1: Neuropsychological assessment of RY



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10


Fig. 1.
T2 weighted 3D coronal images of patient RY showing normal hippocampi
bilaterally.



3
.
Material and
Method
s

A customised paradigm was developed to profile RY’s
ALF during the first 4 hours

after
learning
, and
to
investigate the impact of repeated recall on retention measured at 24 hours.
Memory for word
-
pairs was tested using cued
-
recall and forc
ed choice recognition at four

time intervals during the same day (5
min, 30 min, 55 min, 4 hours), and after a night’s
sleep. A repeated measures design was used. All participants took part in all conditions in the
same order (no counter
-
balancing).


3
.1

Normal Controls

RY’s performance was compared to 5 age
-

and
IQ
-
matched control subjects who were
free of neurological or psychiatric disorders. RY: age at time of testing

(in
2007
)

= 68,
Wechsler Test of Adult Reading (
WTAR
)

IQ=116. Control group: N=5; 2 males, 3 females
1
,
mean age 66.3, SD 4.9 years, mean WTAR IQ
=117.88, SD 6.29. All participants gave
informed written consent to take part in the study, which was approved by the local ethical
committee.




1

Comparison of the scores for male and female n
ormal controls found negligible
difference
s
; it is
therefore concluded that the inclusion of three females

in the control group did not contribute
significantly to the difference found between RY and the controls
.

RUNNING HEAD: ACCELERATED LONG
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11


3
.
2
Stimuli & Procedure

Pilot study data indicated that to avoid stressing or fatiguing participants
,

a maximum of
12 word pairs could be learnt in
any
one
single
learning period, each lasting approximately
10 minutes
. To ensure that the total procedure
(except the 24 hour test)
from start to finish
could be completed within a single visit it was necessar
y to restric
t the number of learning
period
s to 3. With 3 l
earning period
s of 12 word
-
pairs each the total number of word
-
pairs to
be learnt was 36.
A total of 4 word
-
pair lists were required; one to be
recalled at 5 minutes
and at all other time intervals

(repeatedly recalled list), and
one each to be recalled after 30
min, 55 min and 4 hours.
As 4 lists were required,

and 36 word
-
pairs were available,
the
length of each list was therefore
set at
9 word
-
pairs.

Additional words were required as alternate an
swers (foils) for two 4
-
choice FCR tests.
For each FCR test the first word of a pair was presented, followed by the correct paired
associate (target) and three foils. Different foils were used for each test; 6 foils were
therefore required for each word pa
ir.
With 6 such foils
per word
-
pair, and 36 word
-
pairs,
the total number of words
(word
-
pairs and foils)
required was 288.

All words were 1 syllable, 4 to 6 letters, and were nouns with no pronunciation variants.
The 288 words were assigned to 8 lists of length 36 such that the parameters word length,
familiarity, concreteness, imageability and frequency were
matched in the va
rious lists. The
first two lists
were then combined to produce 36 word
-
pairs. Any word pairs with obvious
semantic relationships were re
-
paired randomly. Word
-
pairs were then assigned randomly to
produce the required the 4 word
-
pair lists, each of 9 word
-
p
airs length (e.g. TROOP
-
SHAWL). The words from th
e remaining six lists were randomly assigned
to provide the 6
FCR foils per word
-
pair.

The word
-
pairs from the
four lists were interleaved equally ac
ross the three learning
periods. The stimuli for each lea
rning period therefore consisted of 3 pairs from each list.
The pairs from each list were also
interleaved within each stimul
us

set to provide the order
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12

for first presentation.
This interleaving of material from the 4 lists
both
across and
within
learning
period
s
mi
nimised the impact of
task learning effects
, pro
-
active interference,
fatigue, and any sub
-
clinical epileptiform activity.

The word pair lists were learnt using a two
-
phase process. In the first
study
-
only

phase
word pairs were presented on a com
puter screen in a fixed sequential order, displayed in
black capitals on a white background. Each pair was displayed for 7 seconds. Phase two,
using an
anticipation
-
plus
-
study

procedure, followed immediately. The pairs were processed
in a random order

to avoid order effects
. The first word in each pair was presented and the
participants were required to type the second word. Immediate feedback was then provided
(“Correct. The correct pairing is:” or “Incorrect. The correct pairing is:”) which included
display of the correct pairing for two seconds. After displaying all pairs
,

the process
repeated, using a new random order. Once any individual pair had been answered correctly
three ti
mes it was removed from the stimul
us

set
. Once all pair
s had been remov
ed from the
set

(100% learning criterion) the learning session was complete.

Each learning period was followed by a 5 minute rest, and then a test period. During the
rest period participants performed a distraction task (pencil and paper maze completion),

to
prevent rehearsal.
Once all material had been learnt the gap between tests increased
throughout the procedure.
During t
hese longer gaps
participants were engaged in general
conversation. During the final gap, before the 4 hour test period, participant
s were
accompanied to lunch by the researcher.
Each
test period consisted of
cued
-
recall

followed
by

FCR testing. Word
-
pairs were allocated to each test interval such that each item was
tested at the
correct delay (refer to Figure 2

for full detail).


RUNNING HEAD: ACCELERATED LONG
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13


Fig. 2. Timings for learning and test intervals.


List 1 was cued
-
recalled
tested
at each test interval (5mins, 30 mins, 55mins, 4hrs). The
remaining lists (Lists 2, 3 and 4) were tested at one test interval only; List 2 was tested at
30mins,
L
ist 3 at 55mins and
L
ist 4 at 4 hrs. These
three
tests, combined with the 5 minute
interval result from List 1, were intended to profile the onset of RY’s ALF.

The purpose of
L
ist 1 was to check whether it was possible to limit the impact of ALF by
repeat
edly recalling material, without any re
-
presentation. This maps to real
-
world scenarios
where repeated presentation is impossibl
e but repeated recall is possible
. For this reason
FCR testing was omitted for L
ist 1

until the final test at 24 hours delay
,
thus eliminating

any
possibility that re
-
presentation of the correct answer during such an FCR test
might

contaminate the measurement of the benefits of repeated recall.
Lists 2, 3 and 4, which were
not repeatedly
-
recalled, were tested with both cued
-
recal
l followed immediately by FCR.

RUNNING HEAD: ACCELERATED LONG
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14

The 5 minute
test
interval was included as a check of initial encoding, to protect against
the possibility that short
-
term memory may have been used for any of the three recalls used
as criterion for initial learning. This a
lso simulated the first recall within a possible repeated
recall strategy for protection against the impact of ALF, in which it was expected that the
patient would be advised to perform the first recall a few minutes after learning.

As well as the

testing
detailed above, a
ll 4 complete lists were also cued
-
recall and FCR
tested at 24 hours, after one
night’s sleep (refer to Figure 3

for a summary of test regim
e).
The initial learning period

started at 10:00am, with the 24 hour test period starting at
10:00a
m the next morning after a night’s sleep.


List

Test Delay


5 mins

30 mins

55 mins

4 hours

24 hours

List 1

Cued
-
recall

Cued
-
recall

Cued
-
recall

Cued
-
recall

Cued
-
Recall &
4FCR

List 2


Cued
-
Recall &
4FCR



Cued
-
Recall &
4FCR

List 3



Cued
-
Recall &
4FCR


Cued
-
Recall &
4FCR

List 4




Cued
-
Recall &
4FCR

Cued
-
Recall &
4FCR


Fig. 3. Summary of test regime.


While initial learning to criterion was performed using a computer, r
ecall testing was pen
and paper based. Participants were given a sheet with
the first word from
a number of
pairs

from the relevant lists presented in random order in one column, followed by one blank
column. Participants were asked to recall any matching second words, and to place these in
the empty column.
For example, for the
pairing TROOP
-
SHAWL the cue provided was
TROOP, and the accurate response was SHAWL.
Morphological errors (eg., “
troops

instead of “
troop
”) were scored as correct. Only words matched to the correct associate were
counted as accurate responses.

No feedback

was given to the participants regarding their
performance, and correct answers wer
e not presented. An upper time limit for each test was
RUNNING HEAD: ACCELERATED LONG
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15

set, calculated to allow 15 seconds per word
-
pair.
However, in practice every participant
finished well within the all
otted time

without any prompting
.

FCR testing was also pen and paper based. Participants were given a sheet with a number
of
first
words from
word
-
pairs from
the relevant lists presented in random order. Four
options for the second word in the pair were pr
esented beside each
first word. Participants
place
d

a tick beside their choice.
For example, for the pairing TROOP
-
SHAWL the cue
provided was TROOP and the four options were FLOAT, BROOM, FROST, SHAWL.
Participants were instructed to answer all questions,
and to guess if they could not recall the
correct matching word. They also placed a tick in either a Remember, Know or Guess box,
to indicate whether they remembered the pairing,
did not remember the pairing but did kno
w
the correct answer (e.g. one foil
seem
ed

more familiar, or
they kn
e
w
by a process of
elimination), or whether the answer was a pure guess (RCA paradigm; Gardiner & Java,
1993).

As with the cued
-
recall testing, no feedback was given to the participants regarding
their performance, and corre
ct answers were not presented.
An upper time limit for each test
was set, calculated to allow 15 seconds per word
-
pair. Every participant finished well within
the allotted time without any prompting.

T
o minimise fatigue and
task
-
learning effects the it
ems
were randomly interleaved
within

each test interval and the order was changed for the 24 hour test.

Initial briefing included a familiarisation trial using the software to learn a list of three
word pairs, not present in any of the othe
r lists. This was fo
llowed by
trial
cued
-
recall and
FCR test
s

for this list. At all stages
,

participants were instructed not to rehearse the word
-
pairs between sessions. A post sleep self
-
report questionnaire was used before the 24 hour
test, to monitor the number of hours sl
ept and any disturbance of sleep.


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16


4.

Results

All participants
, including RY,

reported a minimum of 7 hours sleep overnight.
To
provide an indication of
initial

learning the mean duration and number of trials
to reach
criterion
for each learning session,
for RY and normal controls, were compared

(
Fig 4
)
. RY
performed simi
larly to controls
on both criteria

(mean duration,
t
(4) = .81, p = .23
; number
of trials
, t(4) = .30, p = .39
) indicating intact acquisition of new material
.












Fig. 4. Average
trials and duration per learning period

(error bars represent 1 SD)
.


Cued
-
recall scores were compared using Crawford and Garthwaite’s (2002) method for
comparing a single case with a group of control subjects. For cued
-
recall of non
-
repeatedly
recalled word
-
pairs RY’s performance was within 1 SD of the control mean at 5 min
utes
(RY score =
7
; NCs: Mean =
8
, Range =
7
-
9; t(4
) =
.91
, p
=

.21
)
and 30 minutes

(RY score =
5; NCs: Mean = 6.6, Range = 5
-
9; t(4) = .80, p = .23)
, but beyond that point
indicated
accelerated forgetting, falling

significantly below controls at

55 minute
s
(RY score = 2; NCs:
Mean = 5.6, Range = 4
-
7;
t(4) = 2.88, p = .02)

and 4 hours (RY score = 2; NCs: Mean = 5.6,
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17

Range = 5
-
8; t(4) = 3.52, p = .01)
.
This pattern was confirmed by analysis of forgetting rates
using the following formulae: 5 minutes to 30 mi
nutes forgetting = (5mins recall


30mins
recall)/(5mins recall); 30 minute to 55 minutes recall = (55mins recall


30mins
recall)/(30mins recall). This relative rate of forgetting analysis minimises the impact of any
differences between RY and controls’ a
bsolute performance. RY’s forgetting rate was
normal between 5 and 30 minutes (t(4) = .79, p = .24), but became significantly greater
between 30 and 55 minutes (t(4) = 3.30, p = .01).

In contrast, for cued
-
recall performance of repeatedly recalled material
, RY’s
performance remain
ed

close to the control mean for all time periods. To allow direct
comparison of the results for repeatedly and non
-
repeatedly recalled material, both sets of
data ar
e displayed together in Figure 5
. This clearly highlights
both
RY
’s accelerated
forgetting for non
-
repeatedly recalled material and a reinforcement or consolidation effect
for repeated cued
-
recall.


Fig. 5. Cued
-
recall performance for
non
-
repeatedly and repeatedly recalled material (error
bars represent 1 SD)
.

0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
5 mins
30 mins
55 mins
4 hours
24 hours
Cued
-
Recall Score (max=9)

Delay

Controls (N=5) repeated recall
RY repeated recall
Controls (N=5) non-repeated recall
RY non-repeated recall
*

p < .05

*

*

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18


For recognition of
both repeatedly and
non
-
repeatedly recalled word
-
pairs RY
as well as
normal controls performed at ceiling at all time points
.

Figure 6

presents the breakdown of
FCR responses between “
R
emember”, “
K
now” and “
G
uess” categories for non
-
repe
atedly
recalled word
-
pairs at each test delay, and for repeatedly recalled word
-
pairs tested at 24
hours

(repeatedly
-
recalled pairs were only FCR tested after 24 hours; refer to section 3.2)
.
Normal controls maintain a high level of
R
emember responses
across all time points. In
contrast
,

while

the proporti
on of RY’s responses which are
R
emember is
in the normal range
at 30 minutes,
it
is then impaired at all other time points (
30mins test, t(4) = 1.62, p = .09;
55mins test, t(4) = 7.63, p < .01; 4hrs te
st, t(4) = 3.69, p = .01;
repeatedly recalled material
tested at
24hrs, t(4) = 3.15, p = .02
), indicating a
rapid deterioration in the recollective aspect
of familiarity
between 30 minutes and 55 minutes.
The fact that RY’s remember response
s at
24 hours
e
ven
for repeated recalled material are significantly less frequent than those of
normal controls indicates that repeated recall failed to maintain the subjective quality of
RY’s recognition at normal levels.










Fig 6.
Comparison of percentage of
correct FCR responses marked as Remember, Know or
Guess.


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19

To investigate the time limits of the memory protection provided by a single recall and
FCR, and to allow any such benefit to be compared with that provided by repeated recall at
multiple intervals,

material which was not repeatedly recalled was cued
-
recall tested a
second time after 24 hours.

Figure

7

summarises this data,
plotting performance at the 24hr point as a function
of the
original learning regime
.

RY’s 24 hour cued
-
recall performance for the repeatedly recalled
material was within normal limits (just over 1SD below control mean, t(4) = 1.28, p = .14),
while performance for all other lists was significantly impaired (30mins test, t(4) = 2.45, p =
.04
; 55mins test, t(4) = 2.31, p = .04; 4hrs test, t(4) = 6.49, p < .01). Repeated cued
-
recall
was the only reinforcement schedule that maintained RY’s
recall
performance at normal
levels.




Fig. 7.
24 hour cued
-
recall performance as function of previous
cued
-
recall and FCR
schedule

(error bars represent 1 SD)
.






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20

5.

Discussion

The current study extended
an on
-
going case study of a patient
displaying sub
-
clinical
TLE and
ALF
. Three
unresolved aspects of ALF

were addressed
:
the timeframe of onset,

the
role of sleep
, and the use of repeated recall

as a protection against the impact of ALF. Using a
word
-
pair association paradigm it was found that RY’s initial learning and performance at 30
minutes were normal, but by 55 minutes both his cued
-
recall p
erformance and the subjective
quality of his recognition memory were significantly impaired compared to matched controls.
Since the patient remained awake and seizure free throughout the test period it appears that
neither
disruption of consolidation proce
sses during
sleep nor clinically observable seizures
are necessary conditions for RY to experience ALF. For word
-
pairs recalled at multiple time
-
points within the first 4 hours performance remained within the normal range to at least 24
hours, showing that

such repeated recall had a protective effective. In contrast a single recall
within the first 4 hours was insufficient to generate such protection.

The current study
directly address
ed

the timeframe of ALF onset by measuring memory
performance during the
first few hours after learning.

For cued
-
recall of non
-
repeatedly

recalled word
-
pairs, RY performed in the normal range

at delays of
up to 30 minutes, but
displayed accelerated forgetting from that time on,
with his scores
becoming significantly
i
mpaired by 55 minutes. This suggests
the onset of RY’s ALF occurs somewhere between 30
and 55 minutes.

Such a forgetting rate is consistent with the data from a pilot study which
demonstrated significantly degraded
cued
-
recall of word
-
pair associations aft
er a 12 hour
delay (
McGibbon, Jansari & Gaskell, 2008
). However, it indicates

a more rapid
memory
loss
than
detected
in previous recall t
ests
(Jansari et al., 2010)
,
which have shown RY performing
well above floor at 24 hours and taking

around one week to
reach floor.
However,
these
previous tests have involved short stories and visual figures; RY’s recall of word lists or word
pairs over extended periods has not been tested before. A short story consists of multiple items
of information
combined

together i
n an integrated fashion, each item linking (and thus
providing recall cues) to multiple other items in the story. For the story to make sense it will
RUNNING HEAD: ACCELERATED LONG
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21

also link to existing general knowledge and schemas, and this semantic context provides yet
more recall cu
es. In this way, short story recall is a close approximation to real
-
world episodic
memory. In contrast the items in this study’s word
-
pair lists were deliberately chosen to avoid
any possible semantic links between pairs and between items in each pair. Th
is minimises the
risk of participants’ prior associations impacting the results, a general approach dating back to
Ebbinghaus (1885). Many studies have shown that recalling meaningless “pure” information is
harder than recalling meaningful material (e.g. B
ower, 1969). It may be that a word
-
pair recall
test highlights forgetting of associations in a way that a short story test does not, and therefore
provides a more immediate diagnosis and measure of RY’s ALF
, and a “cleaner window” into
the ALF itself
.
An a
lternative

explanation for the different ALF timescales detected with
different material is that ALF over short and long delays reflect two different processes, as
proposed by Wilkinson et al. (2012)
, with forgetting over short period linked to hippocampal

pathology while forgetting over longer periods is associated with ongoing epileptiform
activity
. However, it is
currently
not clear why different material should be differentially
suscep
tible to two
processes

in this way
.

A final
explanation for the relatively rapid degradation in RY’s cued
-
recall performance
in the current study
could be poor initial encoding; however there is evidence against this.
Firstly, the duration of RY’s learning sessions and number of presentations requir
ed to learn
to criterion were both within the normal range. Secondly, all participants learnt to the same
criterion. And finally, RY’s intact performance at 5 minutes and 30 minutes indicate that his
initial encoding is adequate. It is therefore unlikely t
hat his poor performance at 55 minutes
is due to inadequate encoding.


With respect to the role of sleep in ALF, th
e current study
provide
s

clear evidence of
ALF occurring during the same day as learning, before sleep had occurred.
With one
exception
(Wilkinson et al., 2012), previous studies have only detected ALF

after
at least
one
night's sleep. Since for normal controls sleep provides a protective effect for newly learnt
material (e.g. Ellenbogen, Hulbert, Stickgold, Dinges & Thompson
-
Schill, 2006)

it is
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22

possible that in ALF patients disturbed sleep may result in a failure to obtain this benefit. If
this were the only cause of ALF then normal controls would have no advantage over ALF
patients during a waking study. The fact that RY showed ALF within

55 minutes argues
against this as a sole cause in his case. This is interesting considering the apparent link
between ALF and sleep in TEA (Butler et al., 2007). It may be that ALF in TEA and non
-
TEA patients have separate causes, or alternatively the noc
turnal seizure activity Butler et al.
suggest as a cause of disrupted consolidation may also

be

present in RY
at a sub
-
clinical
level
during the waking state.

Further testing incorporating EEG monitoring would help
isolate the cause of ALF in cases like RY
.

Evidence for the impact of repeated recall on memory consolidation and its use in
countering the effects of ALF
comes from the results for cued
-
recall of repeatedly recalled
word
-
pairs.
In contrast to the accelerated forgetting seen for non
-
re
peatedly recalled
material, these results
show intact retention across the

whole 24
-
hour period
. As the gap
between
successive
test intervals increases significantly over the course of the 24 hours
,

this
result indicates a genuine reinforcement or consoli
dation effect for repeated cued
-
recall,
rather than merely a refresh at each recall followed by
the
same rate of forgetting.
For
example,
multiple repeated recalls within the first 4 hours provided protection against ALF
for at least the next 20 hours (
the

gap between the 4 hour test point and the next test point at
24 hours).

This consolidation for repeatedly recalled material is consistent with previous results for
RY’s recall of sho
rt stories (Jansari et al., 2010) and with
evidence that memories of
ALF

patients remain intact for information frequently recalled or rehearsed over many years

(Mayes et al., 2003)
, suggesting that frequent recall can provide protection against the
impact of
ALF
.

As far as we are aware this series of studies with RY is the
first

to

investigate the benefits of repeated recall in ALF, not only at different timeframes but also
for different materials.
These findings raise the possibility that a repeated recall strategy
could be employed by patients to counteract the effects of
ALF, much as a spaced retrieval
RUNNING HEAD: ACCELERATED LONG
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23

technique can be used to teach new information to patients

with dementia

(Brush & Camp,
1998).

For short stories a single recall at 30 minutes was sufficient for RY to extend
retention to 24 hours (Jansari et al., 2010). How
ever for word
-
pair associations multiple
cued
-
recalls were required during the first 4 hours to achieve the same retention. This
indicates that the timing and frequency of the recalls in any such strategy
needs to be
nuanced and
would be partly determined
by the type of information to be retained.

In contrast to cued
-
recall, RY’s recognition perf
ormance (FCR) was
at ceiling
at all time
points

for both repeatedly and non
-
repeatedly recalled material
.
At first viewing, RY’s intact
FCR scores suggest his recog
nition does not degrade over the timeframes of this study.
However, a closer inspection through use of the RCA paradigm (Gardiner & Java, 1993)

showed that

the subjective quality of RY’s recognition does degrade, with a shift
from

R
emember”
to “
K
now” and

G
uess” responses occurring more rapidly than for normal
controls. This deterioration becomes significant over the same time period (between 30 and
55 minutes) as
the
deterioration of cued
-
recall.
This deterioration in the subjective quality of
RY’s recogn
ition memory despite intact performance on
basic
FCR testing

concurs with his
performance for

recognition of unfamiliar faces (Jansari, Davis, Firminger, Ward & Kapur,
2005).

Anecdotally it appeared that i
n many cases RY’s FCR scores were sustained
primari
ly
by
familiarity with the individual items (target
versus
foils) rather than for the

actual

word
pairings

per se
. For example, on multiple occasions he reported knowing that he had not seen
any of the foils before
which
,

combined with some familiarity for the target, helped him to
identify the correct response
even though he had no recollection of the target’s pairing with
the cue word. This
suggests

that memory of the association or relation between a pair of
words is be
ing lost before
memory for the individual items.

The
possible

dissociation between RY’s recall and recognition
memory (shown by
falling
cued
-
recall scores while FCR scores remain at ceiling) and between memory for
relational information and item familiari
ty (suggested

by the shift from
R
emember to
K
now
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24

responses in FCR)

may

help in theorising the location of any structural damage or focus of
sub
-
clinical epileptiform activity

causing
his

ALF
. Dissociations between recollection and
recognition have
frequently been found, with both lesion s
tudies (
Holdstock et al., 2002) and
neuroimaging of healthy participants during encoding (Ranganath et al., 2003; Davachi,
Mitchell & Wagner, 2003)
as well as for
retrieval (Eldridge, Knowlton, Furmanski,
Bookheimer

& Engel, 2000)
. These studies have

indicat
ed

that the hippocampus is
selectively involved in recollection, while the rhinal cortex, and possibly other areas within
the parahippocampal gyrus, support familiarity
-
based recognition. Similarly, previous
stud
ies have indicated that the hippocampus supports relational processing while the
entorhinal and parahippocampal cortices support item based processing (Davachi & Wagner,
2002). Taken together this evidence suggests the process or damage causing RY’s memory

problems may impact both the hippocampus and parahippocampal gyrus (since both
recollection and recognition are impai
red relative to controls), but a
ffects the hippocampus
more severely (since recollection and relations between items are
impacted
first).

However,
the fact that no structural abnormalities have yet been found suggests

that

if the cause is
structural then it is
either
very subtle

or undetectable by current neuro
-
imaging techniques
.

Existing consolidation theories suggest that both semantic an
d episodic memory are
intially reliant on the MTL, with traces in this structure providing an index that link the
components of a memory together into a coherent whole. Alvarez and Squire postulate that
during secondary consolidation indexing of both seman
tic and episodic memory shifts to the
neocortex, such that both memory types become independent of the MTL (Standard
Consolidation Theory; Alvarez & Squire, 1994). In contrast Nadel and Moscovitch argue
that while the indexing of semantic memory may reloca
te to the neocortex, episodic memory
indexing remains reliant on the MTL i
n
defin
i
tely, and that episodic memories are
consolidated through setting up of multiple traces (Multiple Trace Theory; Nadel &

Moscovitch, 1997). RY's intact memory for word
-
pair associations at 5 minutes and 30
minutes suggest that memory encoding and the initial storage of index information in the
RUNNING HEAD: ACCELERATED LONG
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25

MTL are happening normally. However evidence of accelerated forgetting by 55 minu
tes
suggests degradation of MTL
-
based traces before secondary consolidation processes can
transfer this information to other locations (Standard Consolidation Theory) or before
multiple traces can be setup in the MTL (Multiple Trace Theory).
This could be
due to a
failure of a process than maintains memory traces, or to active disruption d
ue to epilepsy
.
The fact that RY’s memory did not improve
after

medication
with anti
-
epileptic drugs
(Jansari et al., 2010)
counts against
epilepsy as the
primary
cause. H
owever

it re
mains
possible that drug treatment
has
not eliminated sub
-
clinical activity that is causing his
ALF
.
Indeed, even where interictal EEG abnormalities are not present, this does not rule out the
possibility of ongoing epileptiform activity as thi
s may be occurring in deep temporal
structures such that it does not show on routine EEG analysis (Bilo et al., 2009).
Alternatively, it is possible that a lifetime of sub
-
clinical epilepsy may have caused
subtle
structural or functional damage

which has s
o far remained undetected
. Further analysis
(EEG, MRI
, MEG)
will be required to investigate these possibilities.

If

RY’s
memory
problems are caused by disruption of MTL based traces before
secondary consolidation can occur, then possible strategies to min
imise the impact of his
ALF

should focus on refreshing traces through repeated recall or rehearsal until secondary
consolidation has taken place. This suggestion is
supported by
evidence of consolidation
through repeated recall

in the current and previous
studies (Jansari et al., 2010)
.

In conclusion,
the current study provides the first evidence that onset of ALF can occur
in the first few hours
following
normal

initial

learning

and retention over the period covered
by standard clinical tests
.
This suggests that, at least for RY,
ALF reflects disruption of
secondary consolidation processes that occur relatively soon after learning.

In
RY
’s case

it
was possible to detect the effects of ALF at 55 minutes using word
-
pair associat
ions. This
suggests

that it may be possible to develop a standard test that can detect ALF within a single
clinical visit.
For example,
to capture the ALF within one hour, then the above procedure
could be adapted to simply one learning session lasting approximately 10 minut
es followed
RUNNING HEAD: ACCELERATED LONG
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26

by a 50 minute gap during which other non
-
verbal clinical tests could be
performed before
recall testing was completed.

Evidenc
e of ALF
occurring on the same day as initial learning

indicated

that
even if
disruption of memory consolidation proc
esses that occur during sleep
contributes to RY’s
rapid forgetting,

it cannot be the sole cause
.
E
vidence
was found
that
repeated recall can be effective

in counteracting the
impact of ALF
,

suggest
ing

this could
form the basis of a rehabilitation strategy for ALF patients.
Fu
ture

work
is required to
validate effectiveness of this technique with other data types, for example memory of real
life events (episodic memories).

Further work is also required to assess whe
ther these results
generalise to ALF patients as a group.


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27

Acknowledgements

We would like to thank RY and his wife for generously donating their time. We
would also like to thank Dr Gareth Gaskell at the University of York for assistance
with generation of

stimuli, and Dr Peter Nestor, Consultant Neurologist at
Addenbrooke’s Hospital, Cambridge for his advice on RY’s brain scans.

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28

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